We hypothesized that enhancing LRP5 signaling, which is pro-anabolic, would be an effective treatment strategy for patients with Osteogenesis Imperfecta (OI), a genetic disorder that affects nearly 28,000 US citizens. We tested our hypothesis using 4 different mouse models of OI by breeding these mice to a strain that has the high bone mass causing Lrp5A214V allele and by giving a SOST inhibitory antibody (Scl-Ab). We found that enhancing LRP5 signaling, genetically via the Lrp5A214V allele or pharmacologically via Scl-Ab, improved bone properties in each OI model. We now want to determine whether the gains in bone mass and strength from anti-SOST therapy continue to increase as the duration of therapy is lengthened, whether anti-SOST therapy is superior to anti-resorptive therapy in OI mice, and whether increases caused by Scl-Ab will be maintained by consolidating the anabolic response with an anti-resorptive therapy. We will compare Scl-Ab versus Alendronate, and also randomize 12-week-old OI mice that had received vehicle or Scl-Ab to next receive vehicle or Alendronate an additional 12 weeks. We will evaluate bone properties using a variety of measures including multi-fluorochrome labeling and quantitative histomorphometry, high resolution X-ray for fracture, DEXA for bone mineral density and total bone mass, CT for microstructure, and whole femur 3-point bending and vertebral compression for bone strength. We also want to test whether a combination therapy that couples enhancing LRP5 signaling and inhibiting TGF signaling is better than either therapy alone. Studies from several investigators suggest that TGF over-activity is deleterious to bone and is a common occurrence in OI. Also, although we found that enhancing LRP5 signaling significantly improved bone properties in mice with moderate to severe OI, it did not bring their bone properties to those of their wild-type littermates that received the same therapy. Therefore, there is room for further improvement in the way we will treat moderate and severe OI. We will enhance LRP5 signaling in wild-type mice and mice with OI using the Lrp5A214V allele and then randomize the animals to receive the TGF inhibitory antibody 1D11. We will compare bone properties in the wild-type and OI mice, with and without enhanced LRP5 signaling, and with and without TGF inhibition. We hope these proof of principle experiments will show that the improvement in bone properties caused by pharmacologic enhancement of LRP5 signaling is better than by anti-resorptive therapy, does not plateau over time and, if needed, can be consolidated with an anti-resorptive therapy. We also will determine whether a combination therapy that targets two important signaling pathways in bone is superior to targeting either pathway alone. These experiments will create a scientific foundation that will provide guidance regarding which OI patients are most likely to benefit from new therapies and what therapeutic regimens will provide the best outcome.